Brachytherapy devices and related methods and computer program products

ABSTRACT

A low-dose-rate (LDR) brachytherapy device having a spatiotemporal radiation profile includes an elongated body having a radioactive material in a spatial pattern to provide a spatial radiation profile with a radiation intensity that varies along a length of the elongated body. The radioactive material includes at least first and second radioisotopes having at least first and second respective decay profiles that together provide a temporal radiation profile that is different from the first and second decay profiles. The spatial radiation profile and the temporal radiation profile form a net spatiotemporal radiation profile configured to provide a radiotherapy plan for a patient.

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 11/846,075, filed Aug. 28, 2007, now U.S. Pat. No. 7,686,756 whichclaims priority to U.S. Application Ser. Nos. 60/823,814, filed Aug. 29,2006; 60/847,458, filed Sep. 27, 2006; and 60/926,349 filed Apr. 26,2007, the disclosures of which are hereby incorporated by reference intheir entireties.

FIELD OF THE INVENTION

The present invention relates to LDR brachytherapy radiation treatmentmethods, systems and computer program products.

BACKGROUND OF THE INVENTION

Roughly 230,000 new cases of prostate cancer are expected in the U.S.this year. Typically 80-90% of these cases are relatively early stagedisease for which various treatment options are available. Primarytreatment options involving radiation include external beam radiationtherapy, which uses high-energy x-ray beams that intersect the prostatefrom multiple angles, and brachytherapy, in which a radioactive sourceis introduced into the prostate itself. Typical brachytherapy techniquesuse so-called “seeds,” which are small (approximately 0.8×4.5 mm)cylinders that contain a radioactive element in a stainless-steelcasing. A number of seeds, usually ranging from 80-120 seeds, are placedinto the prostate using small gauge needles. The seeds can remain inplace permanently while the emitted radiation decays over time. Thecommon radioisotopes used in the seeds are iodine-125, palladium-103 andcesium-131. The goal of the radiation oncologist is to ensure that thetotal dose received by the cancer cells is sufficient to kill them.Seeds can be placed during an outpatient procedure in a single day andthus present an attractive treatment option for patients versus the manyweeks required for external beam radiation therapy. Good candidates forbrachytherapy seed therapy are typically patients having a PSA value≦10,a Gleason score of ≦7 and low-stage disease (T1c or T2a); however,patients with more advanced stage disease may also be treated withbrachytherapy. In some cases, patients (e.g., with more advanceddisease) may be candidates for brachytherapy plus external beam therapy.The use of seeds has grown rapidly, and long-term survival data for LDRbrachytherapy treatment of the prostate is typically good.

In treating prostate cancer with brachytherapy seeds, it may bedesirable to create a uniform radiation pattern within the prostategland or within a region of the prostate gland. Computer code ortreatment planning software can be used to select the number of seedsand their relative placement so that the desired radiation dose isachieved. This is a relative complex procedure because each individualseed is essentially a “point source” of radiation, and thus theradiation contributions from all of the seeds must be summed to achievethe total radiation dose. When the seeds are placed, great care istypically taken to ensure that they are arranged in the patternspecified by the treatment planning software. However, some deviation inseed placement may occur due to the divergence of needles as they areinserted. See Nath et al., Med Phys 27, 1058 (2000). A more problematicoccurrence is the tendency of seeds to migrate once they exit theinsertion needle [See Meigooni et al., Med Phys 31, 3095 (2004)]. It isnot uncommon for seeds to migrate. In some cases, seeds may be caught inan efferent vessel and become embolized in the lung or excreted withurine. Gross movement of the seeds can create non-uniformities in theradiation pattern and thus potentially compromise the efficacy oftherapy.

In an attempt to mitigate the post insertion migration of brachytherapyseeds, various products have been developed. For example, theRapidStrand™ device from Oncura (Arlington Heights, Ill., USA) is ahollow suture material that contains conventional seeds in a “linkedsausage” arrangement. The suture material subsequently dissolves awayleaving the seeds implanted in the patient. However, the seeds are heldby the suture for a time that allows for healing and better retention ofthe seeds. Various so-called “sleeves for seeds” are also available.Another device that is commercially available from IBA(Louvain-la-Neuve, Belgium) under the trade name Radiocoil™ is a coiledstructure device that contains rhodium metal that is proton-activated toproduce Pd-103. Accordingly, the radioactivity is emitted along theentire length of the device.

Notably, the ability of the radiation oncologist to achieve the highestaccuracy in therapy planning is hampered by the discrete nature of thecurrent “seed” radiation sources due to their limited size andanisotropic radiation patterns. The tendency of seeds to move whenplaced in or near prostatic tissue is a problem that, while notinvalidating this excellent form of therapy, creates a non-idealsituation for planning (e.g., requiring revalidation of the placement byCT scan). For example, migration of seeds to the lungs can result inincidental lung doses that are not favorable.

SUMMARY OF EMBODIMENTS ACCORDING TO THE INVENTION

According to embodiments of the present invention, methods of forming alow-dose-rate (LDR) brachytherapy device include providing a substratehaving a micropattern thereon. The micropattern includes a plurality ofspaced-apart wells. A radioactive material is deposited in at least someof the plurality of wells to provide a radiation profile.

According to further embodiments of the present invention, alow-dose-rate (LDR) brachytherapy device includes a substrate having amicropattern thereon. The micropattern includes a plurality ofspaced-apart wells. A radioactive material is deposited in at least someof the wells.

According to some embodiments of the present invention, a low-dose-rate(LDR) brachytherapy device has a spatiotemporal radiation profile andincludes an elongated body including a radioactive material in a spatialpattern to provide a predetermined spatial radiation profile with aradiation intensity that varies along a length of the elongated body.The radioactive material includes at least first and secondradioisotopes having at least first and second respective decay profilesthat together provide a temporal radiation profile that is differentfrom the first or second decay profiles. The spatial radiation profileand the temporal radiation profile form a net spatiotemporal radiationprofile configured to provide a radiotherapy plan of a patient.

According to some embodiments, a computer program product forcontrolling a radiation profile of a brachytherapy device having anelongated body is provided. The computer program product includes acomputer readable medium having computer readable program code embodiedtherein. The computer readable program code includes computer readableprogram code that determines a net radiation profile having spatial andtemporal components for at least one brachytherapy device having anelongated body. The net radiation profile is based on a radiationtherapy plan for a patient. Computer readable program code is providedthat controls the patterning of a radioactive material along a length ofthe elongated body of the at least one brachytherapy device in a spatialpattern to provide a spatial radiation profile with a radiationintensity that varies along the length of the elongated body. Theradioactive material includes at least first and second radioisotopeshaving at least first and second respective decay profiles that togetherprovide a temporal radiation profile that is different from the firstand second decay profiles, and the spatial radiation profile and thetemporal radiation profile form the net spatiotemporal radiationprofile.

According to further embodiments of the present invention, a method offorming a LDR brachytherapy device includes determining a radiationprofile for the brachytherapy device, and depositing a polymeric sol gelmaterial in a pattern on the device. The polymeric sol gel materialincludes a molecularly dispersed radioisotope. The pattern includes aplurality of spaced-apart, discrete globules, each globule having arespective volume of the polymeric sol-gel material.

According to further embodiments of the present invention, abrachytherapy device includes an elongated substrate and a polymeric solgel material having a molecularly dispersed radioisotope. The polymericsol gel is deposited on the substrate in a pattern. The pattern includesa plurality of spaced-apart, discrete globules, each globule having arespective volume of the polymeric sol-gel material.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1E are schematic diagrams of brachytherapy devices according toembodiments of the present invention;

FIGS. 2A-2B are digital images of micropatterned substrates according toembodiments of the present invention;

FIG. 3 is a block diagram illustrating methods, systems and computerprogram products according to embodiments of the present invention;

FIG. 4A is a schematic diagram illustrating a deposition configurationfor selectively depositing a material on a brachytherapy deviceaccording to embodiments of the present invention;

FIG. 4B is a schematic diagram illustrating a micro-syringe depositionsystem for use with a cartridge of substrates according to embodimentsof the present invention;

FIG. 4C is a top plan view of the substrate cassette of FIG. 4B;

FIG. 4D is a digital image of a micro-syringe pump according toembodiments of the present invention;

FIG. 5 is a schematic diagram illustrating a scanning device forselectively irradiating a brachytherapy device according to embodimentsof the present invention;

FIG. 6 is a schematic diagram illustrating a mask and radiation sourceconfiguration for selectively irradiating a brachytherapy deviceaccording to embodiments of the present invention;

FIG. 7A-7D is a schematic diagram of devices and methods in which aradioactive material is deposited on a fiber according to embodiments ofthe present invention;

FIG. 8A-8D is a schematic diagram of devices and methods in which aradioactive material and a radio-opaque material is deposited on a fiberaccording to embodiments of the present invention;

FIG. 9A-9D is a schematic diagram of devices and methods in which aradioactive material is deposited on a dual-rail backbone fiberaccording to embodiments of the present invention; and

FIG. 10A-10D is a schematic diagram of devices and methods in which anadhesion promotion coating is used to promote adhesion between aradioactive material and the substrate according to embodiments of thepresent invention.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention now will be described hereinafter with referenceto the accompanying drawings and examples, in which embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

Like numbers refer to like elements throughout. In the figures, thethickness of certain lines, layers, components, elements or features maybe exaggerated for clarity. Broken lines illustrate optional features oroperations unless specified otherwise.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, integers, steps, operations, elements,components, and/or groups thereof. As used herein, the term “and/or”includes any and all combinations of one or more of the associatedlisted items. As used herein, phrases such as “between X and Y” and“between about X and Y” should be interpreted to include X and Y. Asused herein, phrases such as “between about X and Y” mean “between aboutX and about Y.” As used herein, phrases such as “from about X to Y” mean“from about X to about Y.”

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

It will be understood that when an element is referred to as being “on”,“attached” to, “connected” to, “coupled” with, “contacting”, etc.,another element, it can be directly on, attached to, connected to,coupled with or contacting the other element or intervening elements mayalso be present. In contrast, when an element is referred to as being,for example, “directly on”, “directly attached” to, “directly connected”to, “directly coupled” with or “directly contacting” another element,there are no intervening elements present. It will also be appreciatedby those of skill in the art that references to a structure or featurethat is disposed “adjacent” another feature may have portions thatoverlap or underlie the adjacent feature.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if the device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of “over” and “under”. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

It will be understood that, although the terms “first”, “second”, etc,may be used herein to describe various elements, components, regions,layers and/or sections, these elements, components, regions, layersand/or sections should not be limited by these terms. These terms areonly used to distinguish one element, component, region, layer orsection from another region, layer or section. Thus, a “first” element,component, region, layer or section discussed below could also be termeda “second” element, component, region, layer or section withoutdeparting from the teachings of the present invention. The sequence ofoperations (or steps) is not limited to the order presented in theclaims or figures unless specifically indicated otherwise.

The present invention is described below with reference to blockdiagrams and/or flowchart illustrations of methods, apparatus (systems)and/or computer program products according to embodiments of theinvention. It is understood that each block of the block diagrams and/orflowchart illustrations, and combinations of blocks in the blockdiagrams and/or flowchart illustrations, can be implemented by computerprogram instructions. These computer program instructions may beprovided to a processor of a general purpose computer, special purposecomputer, and/or other programmable data processing apparatus to producea machine, such that the instructions, which execute via the processorof the computer and/or other programmable data processing apparatus,create means for implementing the functions/acts specified in the blockdiagrams and/or flowchart block or blocks.

These computer program instructions may also be stored in acomputer-readable memory that can direct a computer or otherprogrammable data processing apparatus to function in a particularmanner, such that the instructions stored in the computer-readablememory produce an article of manufacture including instructions whichimplement the function/act specified in the block diagrams and/orflowchart block or blocks.

The computer program instructions may also be loaded onto a computer orother programmable data processing apparatus to cause a series ofoperational steps to be performed on the computer or other programmableapparatus to produce a computer-implemented process such that theinstructions which execute on the computer or other programmableapparatus provide steps for implementing the functions/acts specified inthe block diagrams and/or flowchart block or blocks.

Accordingly, the present invention may be embodied in hardware and/or insoftware (including firmware, resident software, micro-code, etc.).Furthermore, embodiments of the present invention may take the form of acomputer program product on a computer-usable or computer-readablestorage medium having computer-usable or computer-readable program codeembodied in the medium for use by or in connection with an instructionexecution system. In the context of this document, a computer-usable orcomputer-readable medium may be any medium that can contain, store,communicate, propagate, or transport the program for use by or inconnection with the instruction execution system, apparatus, or device.

As used herein, the term “globule” refers to a discrete volume ofmaterial, such as a sol gel material. Globules of material can bedeposited on a substrate or in a micro-well, for example, using amicro-syringe pump or micro-pipette according to embodiments of thepresent invention. In some embodiments, the volume of material inglobule can be controlled, for example, with an accuracy of better than10%. Typical sizes of globules are between 5 and 500 nanoliters.

According to some embodiments of the present invention, a low-doseradiation (LDR) brachytherapy device is provided. The device can includea micropattern of a radioactive or activatable material on a substrate.In some embodiments, the micropattern includes a plurality ofspaced-apart wells on the substrate. A radioactive material (or anactivatable material) can be deposited in at least some of the wells.The substrate can be an elongated strand, such as a suture.

In some embodiments, the radioactive material (or activatable material)is selectively deposited (e.g., in globules) in the wells to providenon-uniform and/or discontinuous radiation pattern.

According to further embodiments of the present invention, a pluralityof globules of a radioactive or activatable material are deposited on asubstrate such that the radioactive or activatable material forms aradiation profile. The substrate may include a micropattern, such as awell pattern for receiving the radioactive or activatable materialtherein or the substrate may be devoid of a pattern (e.g., the substratemay be essentially flat or smooth). Examples of suitable substratesinclude a suture, such as a monofilament suture, or other biodegradableor non-biodegradable material that is biocompatible and may be implantedin a patient, such as a glass fiber or a metal fiber. Biodegradablematerials include, but are not limited to, polydioxanone, polylactide,polyglycolide, polycaprolactone, and copolymers thereof. Othercopolymers with trimethylene carbonate can also be used. Examples arePDS II (polydioxanone), Maxon (copolymer of 67% glycolide and 33%trimethylene carbonate), and Monocryl (copolymer of 75% glycolide and25% caprolactone). Non-biodegradable materials include nylon,polyethylene terephthalate (polyester), polypropylene, expandedpolytetrafluoroethylene (ePTFE), glass and metal (e.g. stainless steel),metal alloys, or the like.

In some embodiments, a low-dose radiation (LDR) brachytherapy device isformed by determining a radiation profile for the device based on apatient radiation treatment plan and depositing a polymeric sol gelmaterial on the device in a pattern. The polymeric sol gel material caninclude a molecularly dispersed radioisotope. The pattern can include aplurality of spaced-apart, discrete globules, each globules having arespective volume of the polymeric sol gel material.

In particular embodiments, the polymeric sol gel material can includetwo radioisotopes having respective decay profiles. Accordingly, thespatial pattern and the at least two different decay profiles canprovide a spatiotemporal radiation profile that may be fabricated toimplement a radiation therapy plan for an individual patient. Forexample, ratio of two or more isotopes can be modified to achieve atime-varying radiation profile and can be used to increase theradiobiological effectiveness of the LDR therapy. In some embodiments,different isotopes of the same element can be used.

In some embodiments, the output of conventional radiation therapyplanning software or other suitable radiation therapy plans can be usedto determine the spatial and/or temporal radiation profile for a device.The device can be fabricated using calculated amounts of radioactivematerial, such as a radioactive sol gel material, that may be dispersedin a spatial pattern along a length of an elongated LDR device and/orusing a mixture of two or more isotopes to achieve an appropriatetemporal profile.

The radiation therapy plan and spatial and/or temporal radiation profileof the device can take into account the effects of post-implantationedema, e.g., by adding extra length to the device and/or increasing theradioactivity of the proximal and distal ends of the device that may beimplanted at an outer boundary of the tumor or organ. In particularembodiments, the device can include a filament that can extend outsidethe patient after implantation. The filament may have sufficient tensilestrength to allow a physician to pull the brachytherapy device in theproximal direction to readjust the position of the device afterplacement. Once final positioning is achieved, the filament can besevered close to the skin surface.

In particular embodiments, computer program products can be used todetermine a pattern of radioactive portions and non-radioactive portionsof a device and/or mixture(s) of radioisotopes to create a spatialand/or temporal radiation profile when implanted in the patient and/orto control the fabrication of the brachytherapy device.

Brachytherapy devices may be provided that include a polymeric materialhaving a chemically distributed therapeutic isotope throughout. Thepolymeric material may include a radioisotope, or in some embodiments,the polymeric material can have at least one nuclide that is activatableby exposure to radiation, such as by neutron or proton bombardment. Asused herein, the term “activate” means to make radioactive, for example,by exposure to radiation. The nuclide or the radioisotope can be achemically bound constituent of the polymer, or dispersed uniformlywithin the polymer matrix or chelated to certain substituents of thepolymer without chemical bonding. The nuclide can be a transition metal.In particular embodiments, the brachytherapy device can include anelongated core comprising a polymeric sol-gel material including apolymer chain having at least one nuclide that is activatable byexposure to radiation. The nuclide can be a chemically bound constituentof the polymer chain and can be stoichiometrically distributed in thepolymeric material, or dispersed substantially uniformly within thepolymer matrix or chelated to certain substituents of the polymerwithout chemical bonding. In some embodiments, aspects of themanufacturing process used in creating a radioactive “string” orelongated core can be performed with “cold” material (non radioactive).Then, using an activation pathway, the cold precursor material is made“hot” (radioactive) closer to the time when the end user is ready toutilize the device for therapy.

In specific embodiments, sol-gel processing can be used to formradioactive or activatable materials, e.g., to form polymeric fibers ofthe requisite dimensions for use in LDR (low-dose-rate) brachytherapy.Exemplary sol gels are discussed herein. However, any suitableradioactive material, including radioactive materials or materials thatmay become radioactive through irradiation, may be used.

An example of a brachytherapy device 10 is shown in FIG. 1A. The device10 includes an elongated polymer core 20 and a biocompatible coating 30.The device 10 is sized and configured for implantation into a patient,such as for implantation into the prostate. For example, the device 10can be tube-shaped having a diameter of less than 1 mm or less than 0.8mm. The polymer core 20 can be fabricated using the techniques describedherein, including sol-gel fabrication techniques.

In particular embodiments, the polymer core 20 can be a biocompatiblematerial such as surgical suture material and can have radioactivematerial deposited thereon. The coating 30 can be any suitablebiocompatible coating and may be applied using techniques known to thoseof skill in the art, including dip-coating. The core 20 can be entirelyradioactive, or portions of the core 20 can be radioactive. In someembodiments, the core 20 is non-radioactive, but can be irradiated afterformation to activate at least one nuclide in the polymer to provide aradioactive device.

For example, as shown in FIG. 1B, a device 50 includes a polymer core 60and an optional coating 70. The polymer core 60 includes radioactiveportions 62 and non-radioactive portions 64. In some embodiments, therelative sizes of the radioactive portions 62 and the non-radioactiveportions 64 can be configured for a particular treatment plan for anindividual patient, such as based on the size and positioning of a tumorand the desired radiation pattern for treatment. Typically, a pluralityof devices, such as the device 50, can be made such that each device isconfigured for a specific placement in the body, and so that, inposition, the plurality of devices delivers a desired radiation pattern.

In some embodiments, relatively precise control over the radiationprofile may be achieved by controlling the size and spacing of theradioactive portions 62 and nonradioactive portions 64. In particularembodiments, the radioactive portions 62 may be formed from denselydeposited globules of sol gel material, such as at least 2 to 20 or moreglobules per 5 mm.

For example, as shown in FIGS. 1C-1E, globules 62A of radioactivematerial can be deposited on the core 60. The globules 62A can bedensely deposited in radioactive regions “R” (e.g., in FIG. 1E). In someembodiments, the globules 62A can have a sufficient density so that theradioactive regions “R” have a radiation profile that is substantiallythe same or similar to a continuous line source (e.g., between 2 and 20or more globules per 5 mm). However, it should be understood that anydensity of globules may be used. The globules 62A can be deposited on anunpatterned substrate (FIG. 1E) or on a substrate patterned withmicro-wells that receive the droplet or globules 62A therein (FIGS.1C-1D). The micro-wells can be any suitable shape, including round,rectangular, or square shapes.

In addition, the density and/or volume of the globules 62A can becontrolled and/or calculated to provide radioactive regions “R” as shownin FIG. 1B that have different radiation intensities. The material(s)used to form the globules 62A can also include one or more radioisotopesof a predetermined mixture or two or more materials including differentradioisotopes to provide a desired decay profile for the radioactiveregions “R.”

With reference to FIGS. 1A-1E, it should be understood that the portions64 are referred to herein as “non-radioactive” for ease of presentation;however, the portions 64 may emit a relatively small amount of radiationin comparison with the radioactive portions 62.

In particular embodiments, the core 60 is formed of suture material orother biocompatible material. For example, the radioactive portions 62of FIG. 1B can be formed of a plurality of spaced-apart, discreteradioactive sol gel globules. The sol gel globules may be deposited in apattern on the core 60 or other suitable substrate material. The sol gelmaterial may then cured be, for example, at a temperature of less than150° C., or less than 120° C., to form a radioactive or activatiblexerogel. Two or more radioisotopes can be incorporated into the sol gelmaterial to provide a desired decay profile. More than one sol gelmaterial can be used, and each material can have differentradioisotope(s) therein so that the decay profile can vary along thelength of the core 60.

In certain embodiments, a pre-patterned substrate can be used. Forexample, as shown in FIGS. 1C-1D, a substrate 60 includes a plurality ofmicro-wells 62A with a radioactive material (such as radioactive solgel) received therein. Any suitable micro patterning technique can beused to form the micro-wells 62A on the substrate 60, such asphotolithographically defined wells, stamping, drilling, laser cuttingor molding. The micro-wells 62A can each be filled with the radioactivematerial or the micro-wells 62A can be selectively filled or remainempty to provide a desired radiation profile pattern. In someembodiments, some of the micro-wells can be filed with radio-opaquematerial or other markers configured to increase the visibility of thedevice using medical imaging techniques, such as ultrasound, MRI, orother imaging techniques.

FIGS. 2A-2B are digital images of micropatterned sutures (0.4 mm indiameter in this example) or substrates according to embodiments of thepresent invention. It should be understood that globules may bepositioned in all or some of the wells therein. As illustrated in FIGS.2A-B, the wells can be apertures that extend through the substratematerial.

FIG. 3 illustrates an exemplary data processing system that may beincluded in devices operating in accordance with some embodiments of thepresent invention. As illustrated in FIG. 3, a data processing system116, which can be used to carry out or direct operations includes aprocessor 100, a memory 136 and input/output circuits 146. The dataprocessing system may be incorporated in a portable communication deviceand/or other components of a network, such as a server. The processor100 communicates with the memory 136 via an address/data bus 148 andcommunicates with the input/output circuits 146 via an address/data bus149. The input/output circuits 146 can be used to transfer informationbetween the memory (memory and/or storage media) 136 and anothercomponent, such as a deposition controller, beam controller orirradiation device for selectively patterning a brachytherapy devicewith radiation or radioactive material. These components may beconventional components such as those used in many conventional dataprocessing systems, which may be configured to operate as describedherein.

In particular, the processor 100 can be commercially available or custommicroprocessor, microcontroller, digital signal processor or the like.The memory 136 may include any memory devices and/or storage mediacontaining the software and data used to implement the functionalitycircuits or modules used in accordance with embodiments of the presentinvention. The memory 136 can include, but is not limited to, thefollowing types of devices: cache, ROM, PROM, EPROM, EEPROM, flashmemory, SRAM, DRAM and magnetic disk. In some embodiments of the presentinvention, the memory 136 may be a content addressable memory (CAM).

As further illustrated in FIG. 3, the memory (and/or storage media) 136may include several categories of software and data used in the dataprocessing system: an operating system 152; application programs 154;input/output device circuits 146; and data 156. As will be appreciatedby those of skill in the art, the operating system 152 may be anyoperating system suitable for use with a data processing system, such asIBM®, OS/2®, AIX® or zOS® operating systems or Microsoft® Windows®95,Windows98, Windows2000 or WindowsXP operating systems Unix or Linux™.IBM, OS/2, AIX and zOS are trademarks of International Business MachinesCorporation in the United States, other countries, or both while Linuxis a trademark of Linus Torvalds in the United States, other countries,or both. Microsoft and Windows are trademarks of Microsoft Corporationin the United States, other countries, or both. The input/output devicecircuits 146 typically include software routines accessed through theoperating system 152 by the application program 154 to communicate withvarious devices. The application programs 154 are illustrative of theprograms that implement the various features of the circuits and modulesaccording to some embodiments of the present invention. Finally, thedata 156 represents the static and dynamic data used by the applicationprograms 154, the operating system 152 the input/output device circuits146 and other software programs that may reside in the memory 136.

The data processing system 116 may include several modules, including aradiation treatment planning module 120, a radiation profile controlmodule 124, and the like. The modules may be configured as a singlemodule or additional modules otherwise configured to implement theoperations described herein for planning a radiation treatment plan,determining a spatial and/or temporal radiation profile for a deviceand/or controlling the deposition of radioactive material or irradiatinga device to form a desired radiation pattern. The data 156 can includeradiation data 126, for example, that can be used by the radiationtreatment planning module 120 and/or radiation profile control module todesign and/or fabricate a brachytherapy device.

While the present invention is illustrated with reference to theradiation treatment planning module 120, the radiation profile controlmodule 124 and the radiation data 126 in FIG. 3, as will be appreciatedby those of skill in the art, other configurations fall within the scopeof the present invention. For example, rather than being an applicationprogram 154, these circuits and modules may also be incorporated intothe operating system 152 or other such logical division of the dataprocessing system. Furthermore, while the radiation treatment planningmodule 120 and the radiation profile control module 124 in FIG. 3 isillustrated in a single data processing system, as will be appreciatedby those of skill in the art, such functionality may be distributedacross one or more data processing systems. Thus, the present inventionshould not be construed as limited to the configurations illustrated inFIG. 3, but may be provided by other arrangements and/or divisions offunctions between data processing systems. For example, although FIG. 3is illustrated as having various circuits and modules, one or more ofthese circuits or modules may be combined, or separated further, withoutdeparting from the scope of the present invention.

As shown in FIG. 4A, a sol-gel deposition device 100 is controlled by adeposition controller 102 (e.g., via the I/O circuits 146 of FIG. 3) toform the radioactive portions 62 of the device 60. In particular, thesol gel material can be deposited in a plurality of spaced-apart,discrete globules. Each globule of sol gel material can include aparticular volume of the material so that the pattern of sol gelglobules provide a desired radioactive profile. The globules can haverelatively precisely deposited volumes between 5 and 500 nanoliters orbetween 10 and 200 nanoliters. Two or more radioisotopes may be used toprovide a desired decay profile, which may vary along a length of thedevice. In some embodiments, the volume of the sol gel material can becalculated by the radiation treatment planning module 120 and/orradiation profile control module 124 of FIG. 3. Without wishing to bebound by theory, the amount of radioactive material is generallydirectly related to the amount of radiation emitted. For example, twicethe amount of a radioactive material will generally result in twice theamount of radiation being emitted. Accordingly, in some embodiments,precision deposition can be used to deposit desired amounts ofradioactive material to achieve a particular radiation profile.

The sol gel deposition device 100 can be a micropipette, a microsyringepump, or other suitable extrusion and/or deposition device, such as anUltramicrosyringe II by World Precision Instruments, LTD, Stevenage,Hertfordshire, England. The deposition device 100 can deposit a volumeof material with an accuracy of within 10% or less of the calculatedvolume.

The sol gel material can be formed using a radioactive precursormaterial so that it is radioactive at the time that it is deposited onthe device 60 or, in some embodiments, the sol gel material can in aninactive form during deposition and can be irradiated (e.g., by neutronbombardment) after it is deposited and/or cured to provide a radioactivedevice.

In some embodiments, as shown in FIGS. 4B-4C, a plurality of substrates60 can be positioned on a cassette 66. The cassette 66 includes grooves,and the substrates 60 are positioned in the grooves. The sol-geldeposition device 100 of FIG. 4A can be used to deposit radioactive oractivatable material on the substrates. For example, as shown in FIG.4B, the deposition device 100 is a micropipette having a reservoir 100A,a plunger 100B and a micropipette needle 100C. The plunger 100B pushes adesired amount of material, such as a radioactive sol gel, through theneedle 100C and deposits globules of the material at desired positionson the substrates 60. The deposition controller 102 of FIG. 4A caninclude radiation treatment planning software for controlling thedeposition device 100 to provide a desired radiation profile for thesubstrates 60 as part of a treatment plan. FIG. 4D is a digital image ofa micro-syringe pump and X-Y-Z motion controller for depositingradioactive material on the substrates.

Although embodiments of the present invention are described with respectto deposition techniques, it should be understood that other techniquescan be used to provide a desired radiation pattern. For example, asshown in FIGS. 5-6, a non-radioactive polymer can be activated byradiation using various techniques to form the radioactive portions 62and the non-radioactive portions 64 of the core 60. With reference toFIG. 5, an irradiation beam scanner 80 can be used to bombard the core60 with radiation, such as from a focused proton or neutron beam. Thebeam controller 90 controls the relative position of the core 60 withrespect to the beam scanner 80 to form the desired pattern ofradioactive portions 62 and non-radioactive portions 64. For example,the beam scanner 80 can move horizontally with respect to the core 60 toraster scan the core 60 such that the portions 62 receive more radiationthan the portions 64. The beam controller 60 can control the movement ofthe beam scanner 80 and/or the core 60 to create the desired pattern ofradioactive and non-radioactive portions 62, 64, for example, byscanning relatively slowing on the portions 62 to activate the portions62 and by scanning quickly over the portions 64 to reduce activation ofthe portions 64.

As shown in FIG. 6, the core 60 can be activated with an irradiationsource 82 and a mask 84. The mask 84 selectively permits radiation fromthe source 82 to impinge upon the core 60 to form radioactive portions62 and non-radioactive portions 64.

As shown in FIGS. 7A-7D, an extrusion device 288 (such as amicro-syringe) is used to deposit discrete globules 262 of sol gelmaterial on a substrate 260. The sol gel is heated to form a xerogeland, in some cases, heated further to fuse with the substrate 260 (FIG.7B) to provide radioactive portions 262A, which may be a backbone fiber,silica or suture material. A biocompatible polymer coating 270 can beapplied over the substrate 260 (FIG. 7C) and can be textured to enhanceits visibility in ultrasound imaging (FIG. 7D). Biocompatible polymercoatings include, but are not limited to, polyurethane, silicone,Teflon, parylene, polyethylene, and polyester (PET).

In FIGS. 8A-8B, a radio-isotope containing sol gel globule 262 isdeposited on the substrate 260 in a radiation profile pattern. In FIG.8C, radio-opaque material 273, such as a metallic paste, is deposited sothat the material 273 can increase visibility in medical imagingtechniques, such as ultrasound imaging. A biocompatible polymer coating270 that is optionally textured is applied in FIG. 8D.

As shown in FIG. 9A, a sol gel globule 262 is deposited by the extrusiondevice 288 on the substrate 260A. A second substrate 260B is positionedadjacent the first substrate 260A in FIG. 9B to provide a “dual-rail”backbone fiber, e.g., to increase a surface region for depositing theglobules 262. The cured sol gel material 262A can optionally be usedwith radio-opaque material 273 and/or a biocompatible coating 270 (FIGS.9C and 9D).

As shown in FIG. 10A, a coating layer 261 can be applied to thesubstrate 260 by a deposition device 280 to promote/increase adhesionand/or to limit the lateral spread of the sol gel material. Thedeposition device 280 may be the same or different from the depositiondevice 288 used to deposit the sol gel globules 262 as shown in FIG.10B. The sol gel globules are deposited on the coating layer 261 in thedesired pattern and cured (FIG. 10C). Optionally, a biocompatible and/ortextured coating 270 can be applied (FIG. 10D).

Moreover, although the configurations of FIGS. 7A-7D, 8A-8D, 9A-9D, and10A-10D are illustrated with respect to generally non-patternedsubstrates, it should be understood that the globules of radioactivematerials and/or radio-opaque materials can be deposited in similarpatterns on a micro-patterned substrate having wells for receiving theglobules therein.

In particular embodiments, palladium-103 can be used in a sol gelmaterial and/or encased in a common, biocompatible polymer. Devicesaccording to embodiments of the present invention can be designed towork with existing brachytherapy insertion tools and protocols. Variousmaterials can be used. For example, it may be desirable to design a corethat can biodegrade once the radiation source has decayed. Lighterelements can be used so that there can be less self-shielding of theemitted radiation, which is a complication for metal-encased seeds. Thedevice can be designed so that it can be cut to length easily at theuser site. In some embodiments, the device can be placed throughconventional needles using existing LDR brachytherapy tools. The devicesdescribed herein can be cut to length. The core can contain theactivatable nuclide so that it is a stoichiometrically distributed (andpossibly part of a chemical compound) precursor isotope. Processing ofthe core can proceed without radioactive materials. The core can beactivated by energetic nucleons (protons or neutrons) to form atherapeutic radioisotope. A biocompatible outer coating that protectsthe core and optimizes the mechanical properties core (strength,flexibility) for a specific therapeutic application can be applied. Theouter core can also be textured for increased ultrasound imageappearance.

Sol Gel Formulations

Various radioactive or activatable materials can be used according toembodiments of the present invention. In particular embodiments, a solgel solution was prepared from the following: a) a trifunctional alkylsilane such as isobutyltrimethoxysilane (BTMOS)

and

b) a trifunctional aminoalkyl silane such asN-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAP3),(aminoethylaminomethyl)phenethyltrimethoxysilane (AEMP3), orN-(6-aminohexyl)aminopropyltrimethoxysilane (AHAP3)

The above formulation is an example of a “polar” sol gel (i.e., amolecule with a dipole moment) and has excellent miscibilitycharacteristics with palladium(II) chloride (5 weight %) in hydrochloricacid (10 weight %). The two can be combined to give a clear, homogeneoussolution with very little or no sign of any material precipitation. Incontrast, a combination of palladium(II) chloride with a sol gelsolution prepared from tetraethyl orthosilicate (TEOS) oroctyltriethoxysilane (an example of a “non-polar” sol gel), may lead toa small amount of insoluble material. Radioactive source of palladium,by virtue of its own preparative procedure, can be in the form ofpalladium(II) chloride in hydrochloric acid.

Further, such “polar” sol gels mixed with palladium can be processed tobecome a stable xerogel (and/or a sintered gel).

Without wishing to be bound by theory, polar substituent amino groups in“polar” sol gels such as BTMOS/AEAP3 may provide a hydrophiliccoordination site for palladium without changing the solubilitycharacteristics of either the palladium compound or sol gel, and withoutdisrupting or disturbing the propagation of the polymer chain as thestructure grows. Therefore, the stability and solubility of both thepalladium compound and sol gel solution may not be affected, frominitial mixing to formation of xerogel. It is noted that palladium hasbeen known to have good affinity for amine-containing compounds such asammonium chloride and ammonium hydroxide. According to “Sol-Gel Science”(C. J. Brinker and G. W. Scherer, Academic Press, 1990, p. 244), addinga metal salt to a sol could produce an ion exchange:≡Si—OH+M^(z+)→≡Si—OM^((z−1)+)+H⁺where M^(z+) is an unhydrolyzed cation of charge z. Since the silanolgroups provide adsorption sites for water, and such layer of adsorbedwater prevents coagulation and is responsible for the stability of thecolloid, the removal of SiOH by ion exchange can reduce the amount ofhydration and thus destabilizes the aqueous silica sol.

Hence, in the preparation of a relatively “non-polar” sol gel solutionusing tetraethyl orthosilicate (TEOS) or octyltriethoxysilane, theaddition of palladium(II) chloride (PdCl₂) most likely causes an ionexchange similar to above. The instability thus results can also affectthe solubility of PdCl₂ itself, which explains the frequent observationof precipitated material formation. On the other hand, the palladium ioncan chelate with the amino groups in a “polar” sol gel and stability maynot be affected.

The timing for the addition of PdCl₂ has been found to be anywherebetween immediately to several days after the preparation of a sol gelsolution as demonstrated by the examples below.

Formation of Stable Xerogels from Combination of “Polar” Sol Gel and Pd

A “polar” sol gel solution combined with palladium(II) chloride can becast onto a surface or substrate and dried to a stable xerogel.Initially, the solvent was allowed to evaporate at room temperature for2 hours. This time duration may be longer. Without wishing to be boundby theory, it is believed that a “gentle” escape of solvent in asufficient of amount of time at this low temperature allows the gel tocoalesce into a uniform state which is suitable for subsequenttemperature ramp-ups in forming a clear stable xerogel. Without this“gentle” evaporation of solvent, adverse effects such as cracking ornon-uniform appearance may result. One example of a temperature sequenceimplemented after this room temperature conditioning has been: a) agradual increase to 70° C. and holding the temperature there for 1 hour,followed by b) a second increase to 130° C. and holding the temperaturethere for 2 hours.

This incubation profile generally forms clear, stable xerogel from the“polar” sol gel compositions.

Preparation of a “polar” sol gel may be similar to that published byMarxer, et al. (Chem. Mater. 2003, 15, 4193-4199.), the disclosure ofwhich is hereby incorporated by reference in its entirety.

In some embodiments, a sol gel contains a polar substituent such as anamino group, prepared from a mixture of a) a trifunctional alkyl silaneand b) a trifunctional aminoalkyl silane, and then combined with aradioactive material, such as palladium metal ions. Such “polar” sol gelcan be formed from at least one di- or trifunctional aminoalkyl silane(see below).

The trifunctional alkyl silane can be defined as a silane substitutedwith a single alkyl and 3 alkoxy groups. The alkoxys are consideredfunctional groups as they take part in the polymerization (hydrolysisand condensation) and are replaced in the process. In other words, thealkoxys may be the reactive sites. The alkyl group, which is generallynot a functional group, may be a short-chain carbon unit, e.g., fivecarbons or less, so as to impart less non-polar characteristics to theresulting polymer. A higher degree of polarity of the sol gel may bedesirable for mixing with ionic radioactive sources, such as the ionicpalladium compound.

Exemplary trifunctional alkyl silanes are isobutyltrimethoxysilane(BTMOS), isobutyltriethoxysilane, n-butyltrimethoxysilane,n-propyltrimethoxysilane, n-propyltriethoxysilane,n-pentyltriethoxysilane, ethyltrimethoxysilane, ethyltriethoxysilane,and methyltrimethoxysilane.

The trifunctional aminoalkyl silane can be defined as atrialkoxy-substituted silane with a single alkyl substituent, and thisalkyl unit contains a single or multiple amino groups. The alkylsubstituent may be a shorter chain containing a total of nine carbons orless, or in some embodiments, five carbons or less, and 2 amino groups.

Examples of trifunctional aminoalkyl silanes areN-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAP3),(aminoethylaminomethyl)phenethyltrimethoxysilane (AEMP3),N-(6-aminohexyl)aminopropyltrimethoxysilane (AHAP3),N-[3-(trimethoxysily)propyl]diethylenetriamine (DET3)aminopropyltrimethoxysilane, and aminopropyltriethoxysilane.

In some embodiments, an analogous difunctional diallyl silane can beused in lieu of a trifunctional alkyl silane to provide similarcharacteristics. Likewise, it is possible that an analogous difunctionaldi(aminoalkyl) silane or difunctional aminoalkyl alkylsilane can be usedin lieu of a trifunctional aminoalkyl silane. The resulting polymericstructure and material and gel characteristics may differ slightlydepending on the specific reactants employed to form the sol gel.

It is noted that a “polar” sol gel may be used for incorporating othersuitable radioactive sources, including a radioactive palladium oriodine source in basic pH solution. For example, the source material canbe palladium (Pd-103) (II) chloride in ammonium hydroxide or other formsof palladium. Other radioactive sources (such as iodine) can also beused and added to the sol gel.

After the sol gel solution is cast onto a surface or substrate, it maybe

-   -   a) allowed to evaporate at room temperature (25° C.) for 2        hours,    -   b) heated to 70° C. at a rate of 5° C./min,    -   c) kept at 70° C. for 1 hour,    -   d) heated to 130° C. at a rate of 5° C./min, and    -   e) kept at 130° C. for 2 hours.        To obtain a suitable xerogel formation, one who is skilled in        the art can readily modify the temperature incubation profile to        suit 1) the polymer structure or characteristics of the sol gel        obtained from the selection of a particular trifunctional alkyl        silane (or substitute) and a particular trifunctional aminoalkyl        silane (or substitute), and 2) a specific material configuration        and thickness.        Other Radioactive Materials

Other examples of suitable materials include: 1) Polymerizable materialswhose polymerization is initiated by an external stimulus, e.g., laser,UV, heat, or other energy source; 2) Polymerizable materials whoseinitiation is controlled or regulated. This can be accomplished throughthe use of microencapsulation technology. Thus, a suitable initiator forpolymerization is protected as a microcapsule such that a) themicrocapsule wall or layer is dissolved over time, e.g. 4-5 hours, whichallows sufficient processing time from initial mixing to filling thefiber holes, or b) the microcapsule wall or layer ruptures upon contactwith an external agent when polymerization is called for or when thetiming is deemed appropriate, or c) the microcapsule wall or layerruptures when exposed to an external energy source such as heat or UV.

Accordingly, a line-source and/or a string of radioactive portions alongthe core can be formed for LDR brachytherapy with increased homogeneityin dose delivery. Flexible materials design can increasebiocompatibility, reduce self-shielding effects, and allow for abiodegradable format if desired.

Embodiments according to the present invention will now be describedwith reference to the following non-limiting examples.

EXAMPLE 1

In one illustrative example according to embodiments of the invention,radioactive Pd-103 in the form of palladium(II) chloride is mixed into asol gel. The sol can then be dried to form a xerogel. Once the sol-gelbased, patterned fiber is completed it can be coated with abiocompatible outer coating and sterilized for clinical use.

The pattern of radioactivity in the device could be determined by thespecific requirements for a given patient, e.g., based on brachytherapyplanning software. The proper patterning of the radiation pattern in thedevice can be controlled by a computer configured to translate theclinical brachytherapy prescription into the necessary depositionpattern of radioactivity in the final device.

Small globules (e.g., 5-500 nanoliters) of radioactive sol gel materialcan be deposited into wells in a micro-patterned suture material. Inparticular embodiments, the density of globules is about at least 2globules per 5 mm to about 20 globules per 5 mm or more. In some cases,the globule separations or densities can form a substantially continuousradiation source, i.e., a radiation source with a radiation pattern thatis substantially the same as a continuous line source. In other casesthe radioactivity along the device can be varied so as to produce acustomized, non-uniform radiation pattern.

Once the fiber core is completed, a biocompatible outer coating can beapplied by spraying or dip coating or by gluing or heat shrinking apre-formed tubular material. The biocompatible outer coating could beone of a class of materials used routinely in implantable medicaldevices (e.g., nylon, polyurethane, silicone, or polyester). The finalouter diameter of the coated fiber can ideally be about 0.8 mm so as tobe consistent with existing brachytherapy seed products. This can thenallow for the device to be placed using the same tools currently inplace for LDR prostate brachytherapy. The outer coating can be chosen sothat it helps to maintain the desired flexibility of the device so thatit may be easily placed through the cannula of an insertion needle andso that it is not subject to breaking or irreversible bending.

EXAMPLE 2

To 9.0 mL isobutyltrimethoxysilane (BTMOS) was added 1.0 mL ethanol, 300μl water, and 50 μA 0.5 M hydrochloric acid. The mixture was stirred atroom temperature for 1 hour. 1.0 mLN-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAP3) was then addedand stirring was continued for 1 more hour. The resulting solution canbe used immediately or stored in a refrigerator for up to 45 days.

In order to add palladium(II) chloride, 0.0137 g of 5 wt. % PdCl₂ in 10wt. % hydrochloric acid (Aldrich) was added to 6.14 mL of the sol gelsolution prepared above. This provided a 0.01% Pd (palladium metal) inconcentration.

A 2.0 μl aliquot of the prepared sol gel solution containing Pd wasapplied onto a glass cover slide in a 12 mm circle. It was allowed toevaporate at room temperature for 2 hours uncovered. The material, now aviscous gel film, was then placed inside an oven and the temperature wasincreased to 70° C. at a rate of 5° C./min. The temperature wasmaintained at 70° C. for 1 hour, and then increased to 130° C. at a rateof 5° C./min. It was further held at 130° C. for 2 more hours. Uponremoval from the oven, a clear, hard xerogel film was obtained. Thisfilm showed no or minimal sign of degradation after it was placed in apH 7.4 buffer solution and heated at 50° C. for 40 hours.

Although embodiments according to the invention have been described withrespect to Pd-103, any suitable nuclide for LDR brachytherapy can beused, such as P-32, I-125 and Cs-131.

According to embodiments of the present invention, sol-gel materials canbe used for the incorporation of precursor isotopes (subsequentlyactivated) or radioisotopes themselves to form brachytherapy “strings”in the form of elongated source devices. Spatial and/or temporalprofiles can be provided by selectively depositing radioactive materialsalong the length of the device. The sol-gel techniques described hereinmay be very flexible in terms of what isotopes can be incorporated. Inparticular embodiments, the metallic isotopes are chemically boundwithin the sol gel matrix. Various embodiments according to theinvention are described herein with regard to implementing LDRbrachtherapy device manufacturing.

The sol-gel based string cores can be coated with a biocompatiblematerial (e.g., polyester or nylon), That outer coating may be textured(e.g., with dimples or similar patterns) to enhance the scatter ofultrasonic beams used in imaging. The enhanced scatter allows for easierdetection by ultrasound imagers (typically LDR brachytherapy devices areplaced under transrectal ultrasound guidance).

As noted above, embodiments of the current invention can be employed inthe field of LDR brachytherapy using radioactive isotopes that deliverradiation over an extended period of time from implanted devices. Use ofLDR in treating prostate cancer is common. Use of LDR for breast, head &neck, etc. cancers is under development.

The devices described herein may serve as a sealed-source for thecontainment of the radioisotope(s) as defined by 10 CFR 35.67.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art can readilyappreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. Therefore, it is to be understood that the foregoing isillustrative of the present invention and is not to be construed aslimited to the specific embodiments disclosed, and that modifications tothe disclosed embodiments, as well as other embodiments, are intended tobe included within the scope of the appended claims. The invention isdefined by the following claims, with equivalents of the claims to beincluded therein.

That which is claimed is:
 1. A method of forming a low-dose-rate (LDR)brachytherapy device, the method comprising: providing a substratehaving a micropattern thereon, the micropattern including a plurality ofspaced-apart wells; depositing a radioactive material with amicro-syringe pump and/or micropipette in at least some of the pluralityof wells to provide a radiation profile; and forming a medical devicefrom the substrate and radioactive material wherein depositing theradioactive material comprises depositing a plurality of spaced-apartglobules of the radioactive materials having a density of two or moreglobules per 5 mm and respective volumes for each of the spaced-apartglobules of the radioactive material are between 5 and 500 nanoliters.2. The method of claim 1, wherein the radioactive material is uniformlydispersed at a molecular level.
 3. The method of claim 1, wherein theradioactive material comprises one or more of Pd-103, I-125, Cs-131 andP-32.
 4. The method of claim 1, further comprising coating the devicewith a biocompatible coating.
 5. The method of claim 1, wherein thespaced-apart globules are adhered to the substrate.
 6. The method ofclaim 1, wherein the substrate comprises an elongated body.
 7. Themethod of claim 6, wherein the elongated body comprises a suture.
 8. Themethod of claim 1, wherein the micro-syringe pump and/or micropipetteare controlled by a processor.
 9. A method of forming a low-dose-rate(LDR) brachytherapy device, the method comprising: providing a substratehaving a micropattern thereon, the micropattern including a plurality ofspaced-apart wells; and depositing a radioactive material in at leastsome of the plurality of wells to provide a radiation profile, whereindepositing the radioactive material comprises depositing a plurality ofspaced-apart globules of the radioactive materials having a density oftwo or more globules per 5 mm and wherein the density of thespaced-apart globules of radioactive material is 20 or more globules per5 mm.
 10. A method of forming a LDR brachytherapy device, the methodcomprising: determining a radiation profile for the brachytherapydevice; depositing predetermined volume of a radioactive material in apattern on the device with a micro-syringe pump and/or micropipette, theradioactive material including a molecularly dispersed radioisotope, thepattern comprising a plurality of spaced-apart, discrete globules, eachglobule having a respective volume of the radioactive material, thevolume of each of the globules being controlled by the micro-syringepump and/or micropipette, the globules having a density of two or moreglobules per 5 mm and respective volumes for each of the spaced-apartglobules of the radioactive material are between 5 and 500 nanoliters.11. The method of claim 10, further comprising determining therespective volumes for each of the plurality of globules to provide theradiation profile.
 12. The method of claim 10, further comprisingdetermining a distance between each of the plurality of globules toprovide the radiation pattern.
 13. The method of claim 10, furthercomprising depositing the respective volumes of the globules so that adeposited volume is within 10% of a predetermined amount.
 14. The methodof claim 10, further comprising depositing a biocompatible,nondegradable polymeric coating layer on the device.
 15. The method ofclaim 14, further comprising patterning the coating layer to enhanceultrasound visibility.
 16. The method of claim 10, wherein depositingthe radioactive material comprises depositing the plurality ofspaced-apart globules at a density of two or more globules per 5 mm. 17.The method of claim 10, wherein the device is planar.
 18. The method ofclaim 10, wherein the device is an elongated body.
 19. The method ofclaim 10, wherein the device comprises a plurality of microwells, andthe radioactive material is deposited in at least some of themicrowells.
 20. The method of claim 10, wherein the micro-syringe pumpand/or micropipette are controlled by a processor.
 21. A method offorming a LDR brachytherapy device, the method comprising: determining aradiation profile for the brachytherapy device; depositing a radioactivematerial in a pattern on the device, the radioactive material includinga molecularly dispersed radioisotope, the pattern comprising a pluralityof spaced-apart, discrete globules, each globule having a respectivevolume of the radioactive material, wherein respective volumes for eachof the globules are between 5 and 500 nanoliters.
 22. A method offorming a LDR brachytherapy device, the method comprising: determining aradiation profile for the brachytherapy device; depositing a radioactivematerial in a pattern on the device, the radioactive material includinga molecularly dispersed radioisotope, the pattern comprising a pluralityof spaced-apart, discrete globules, each globule having a respectivevolume of the radioactive material, wherein depositing the radioactivematerial comprises depositing the plurality of spaced-apart globules ata density of 20 or more globules per 5 mm.